Targeting αV-integrins decreased metastasis and increased survival in a nude rat breast cancer brain

Abstract  

Brain metastases commonly occur in patients with breast, lung and melanoma systemic cancers. The anti-α_V integrin monoclonal antibody intetumumab binds cell surface proteins important for adhesion, invasion and angiogenesis in the metastatic cascade. The objective of this study was to investigate the anti-metastatic effect of intetumumab in a hematogenous breast cancer brain metastasis model. Female nude rats received intra-carotid infusion of human brain-seeking metastatic breast cancer cells (231BR-HER2) and were randomly assigned into four groups: (1) control; (2) intetumumab mixed with cells in vitro 5 min before infusion without further treatment; (3) intetumumab intravenously 4 h before and weekly after cell infusion; (4) intetumumab intravenously weekly starting 7 days after cell infusion. Brain metastases were detected by magnetic resonance imaging (MRI) and immunohistochemistry. Comparisons were made using the Kruskal–Wallis test and Dunnett's test. Survival times were estimated using Kaplan–Meier analysis. All control rats with brain tissue available for histology (9 of 11 rats) developed multiple brain metastases (median = 14). Intetumumab treatment either in vitro prior to cell infusion or intravenous before or after cell infusion prevented metastasis formation on MRI and decreased the number of metastases on histology (median = 2, p = 0.0055), including 30 % of animals without detectable tumors at the end of the study. The overall survival was improved by intetumumab compared to controls (median 77+ vs. 52 days, p = 0.0277). Our results suggest that breast cancer patients at risk of metastases might benefit from early intetumumab treatment.

• Content Type Journal Article
• Category Laboratory Investigation
• Pages 1-10
• DOI 10.1007/s11060-012-0942-0
• Authors
  • Y. Jeffrey Wu, Department of Neurology, Oregon Health and Sciences University, 3181 Sam Jackson Park Road L603, Portland, OR 97239, USA
  • Leslie L. Muldoon, Department of Neurology, Oregon Health and Sciences University, 3181 Sam Jackson Park Road L603, Portland, OR 97239, USA
  • Seymur Gahramanov, Department of Neurology, Oregon Health and Sciences University, 3181 Sam Jackson Park Road L603, Portland, OR 97239, USA
  • Dale F. Kraemer, Department of Pharmacy Practice, Oregon State University, Portland, OR 97239, USA
  • Deborah J. Marshall, Ortho Biotech Oncology R&D, Radnor, PA 19087, USA
  • Edward A. Neuwelt, Department of Neurology, Oregon Health and Sciences University, 3181 Sam Jackson Park Road L603, Portland, OR 97239, USA

• Journal Journal of Neuro-Oncology
• Online ISSN 1573-7373
• Print ISSN 0167-594X

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